Field of the Invention
The present invention relates to processes and novel intermediates utilized therein for preparing pharmaceutically useful .alpha.-arylalkanoic acids. In particular, the present invention utilizes novel .alpha.-hydroxy alkyl aryl ketals activated with a labile ester leaving group, which are solvolytically and non-catalytically rearranged to the corresponding .alpha.-arylalkanoic acids or esters, orthoesters or amides thereof. Optional concomitant or sequential hydrolysis of any ester, orthoester or amide formed yields the corresponding and desired .alpha.-arylalkanoic acids.
State of the Art
Numerous .alpha.-arylalkanoic acids (i.e. 2-arylalkanoic acids) have been described and developed and found to be useful as pharmaceutical agents exhibiting anti-inflammatory, analgesic and anti-pyretic activity. For example, U.S. Pat. No. 3,385,386, describes certain 2-phenylpropionic acids useful for their anti-inflammatory activity. Particularly noteworthy of the compounds described therein is 2-(4-isobutylphenyl)propionic acid, known generically as ibuprofen. U.S. Pat. No. 3,600,437 describes 2-(3-phenoxyphenyl)- and 2-(3-phenylthiophenyl)alkanoic acids among other related compounds. Particularly noteworthy therein is the compound 2-(3-phenoxyphenyl)propionic acid, which is known generically as fenoprofen. U.S. Pat. No. 3,624,142 describes (fluoro-substituted biphenyl)alkanoic acids, among which is 2-(4'-fluoro-4-biphenyl)propionic acid. U.S. Pat. No. 3,755,427 describes additional fluoro-substituted biphenylpropionic acids, among which is 2-(2-fluoro-4-biphenyl)propionic acid, known as flurbiprofen. U.S. Pat. No. 3,904,682 describes the compound 2-(6-methoxy-2-naphthyl)-propionic acid, which is known generically as naproxen and is a potent anti-inflammatory compound. Related compounds are described in Belgian Patent No. 747,812. U.S. Pat. No. 3,912,748 describes 5 and 6-benzoxyazoylalkanoic acids possessing anti-inflammatory, anti-pyrretic and analgesic activity. Notable among those compounds is 2-(4-chlorophenyl-5-benzoxazoyl)-propionic acid, known generically as benoxaprofen. Thus, it can be seen that a tremendous variety of useful .alpha.-arylalkanoic acids are known.
Other known, useful .alpha.-arylalkanoic acids are exemplified by 6-chloro-.alpha.-methyl-9H-carbazole-2-acetic acid (carprofen), .alpha.-methyl-9H-fluorene-2-acetic acid (cicloprofen), 3-chloro-o-methyl-4-(2-thienylcarbonyl)-benzene acetic acid (cliprofen), .alpha.-methyl-3-phenyl-7-benzofuranacetic acid (furaprofen), 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzene acetic acid (indoprofen), 3-benzoyl-.alpha.-methylbenzene acetic acid (ketoprofen), 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)benzeneacetic acid (pirprofen), .alpha.-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) and compounds related thereto.
Numerous processes for the manufacture of such .alpha.-arylalkanoic acids have also been described. Such processes have been described in the aforementioned patents and in other patents and in the non-patent literature as well. For example, U.S. Pat. No. 4,135,051 describes a process route for preparing the ester precursors of many of the useful arylalkanoic acids utilizing trivalent thallium salts as reactants. Such a process suffers from the disadvantage that the thallium salts employed are toxic chemicals which must be removed from the final product. U.S. Pat. No. 3,975,431 describes the preparation of .alpha.-arylalkanoic acids from glycidonitriles through enol acylates. U.S. Pat. Nos. 3,658,863; 3,663,584, 3,658,858; 3,694,476; and 3,959,364 describe various coupling methods for preparing arylalkanoic acids. More recently, U.K. Patent publication No. 2,042,543 published Sept. 24, 1980, (corresponding to application Ser. No. 8005752, filed Feb. 20, 1980) describes a process for preparing the ester precursor of arylalkanoic acids from .alpha.-haloalkyl aryl ketones using a metal catalyst for catalytically inducing rearrangement in an acidic, alcoholic medium, the catalyst being silver (I) salts of organic and/or inorganic anions. The high costs associated with utilizing metal catalysts, particularly silver, in a large scale process is an inherent disadvantage to such a process. Accordingly, there remains a need for a simple, economical process for producing .alpha.-arylalkanoic acids of the types described.